Intramolecular Barbier

An alternative, low-yielding route to the tetrahydro-l/7-3-benzazepines 223 from the amides 222 via an intramolecular Barbier reaction has been reported (Equation 29) <2005H(65)2925>. The other significant products from this reaction were the deiodinated noncyclized compounds. 

Organopalladium complexes do usually not transfer a formal carbanion to aldehydes or ketones, but intramolecular Barbier-type reactions of this kind have been observed (Scheme8.2). 

Although Curran s rate data for the reduction of radicals to organosamar-iums allow for an element of predictablity,2 problems can arise when multifunctional substrates are involved. For example, in the attempted intramolecular Barbier reaction of alkyl iodide 13, treatment with Sml2 results in the formation of side product 15 in addition to the expected product cyclohexanol 14 (Scheme 3.7).8 In this case, the p-keto amide motif in 13 is reduced at a rate competitive with alkyl iodide reduction, indicating that there are likely two mechanistic pathways through which the reaction proceeds a thermodynamic pathway initiated by reduction of the R I bond providing the... 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

In 1993, Molander found that in the presence of catalytic Fe(III) salts, Sml2 mediates intramolecular Barbier additions to esters to give cyclic ketones (or cyclic hemiketals, if they prove to be stable).135 Double addition to the ester is not observed, nor is reduction of the cyclic ketone product. This suggests that the tetrahedral intermediate, a samarium alkoxide of a cyclic hemiketal, is partially stable to the reaction conditions and the ketone group is not revealed until work-up. Molander found that both alkyl and allyl halides could be used in the additions (Scheme 5.83).135... 

The Sml2-mediated intramolecular Barbier addition to amides is less common Fadel reported the diastereoselective cyclisation of chloroimide 122,137 while Ha carried out an intramolecular Barbier addition to the carbonyl of cyclic imide 123 (Scheme 5.86).138... 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

Intramolecular Barbier-type reactions occur between carbonyl and halogen groups in the same molecule ... 

The Smh-mediated intramolecular Barbier procedure has been applied to several diverse systems, and in each case has been determined to be superior to other protocols. Suginome and Yamada applied the technique to syntheses of exaltone and ( )-muscone (equation 40). Surprisingly, cyclization in this case generates a single diastereomer. It is claimed that the Smh procedure provides better yields than procedures incorporating Mg/HgCh or n-butyllithium. 

Murray and coworkers have used the Sml2-prthis example was not particularly high, it was the only method among several attempted that proved successful. ... 

Exceptionally clean cyclization can be accomplished by utilizing conjugated enones as precursors for the Barbier reaction (equation 43). High diastereoselectivity is achieved in these reactions, and under the mild conditions required for cyclization the TMS ether protecting group remains intact. It is also interesting that a neopentyl halide is effective in the cyclization. This result would appear to exclude an 5N2-type displacement of an organic halide by a samarium ketyl as a possible mechanism for the Smh-promoted intramolecular Barbier reaction. 

Curiously, the relative stereochemistry between the carboxylate and the adjacent hydroxy group in the Sml2-mediated intramolecular pinacolic coupling reaction is opposite to that observed in the intramolecular Barbier reactions and ketone-alkene reductive coupling reactions discussed previously (compare... 

These examples again have some mechanistic implications in that they appear to rule out cyclization via 5n2 displacement of the halide by a samarium ketyl. However, one cannot distinguish between a mechanism based on allylsamarium addition to the carbonyl versus an electron transfer mechanism as outlined for the alkyl hdide substrates above. Both mechanisms allow for isomerization of the double bond (via 1,3-allylic transposition in the case of an allylmetallic, or configurational instability in an allylic radical in a diradical coupling mechanism) and also provide reasonable routes for generation of butadiene. Further mechanistic work is clearly required in order to provide a more detailed understanding of all of these intramolecular Barbier-type reactions. 

Molander, G. A., McKie, J. A. A facile synthesis of bicyclo[m.n.1]alkan-1-ols. Evidence for organosamarium intermediates in the samarium(ll) iodide promoted intramolecular Barbier-type reaction. J. Org. Chem. 1991,56,4112-4120. 

Molander, G. A., Le Huerou, Y., Brown, G. A. Sequenced Reactions with Samarium(ll) Iodide. Sequential Intramolecular Barbier Cyclization/Grob Fragmentation for the Synthesis of Medium-Sized Carbocycles. J. Org. Chem. 2001,66,4511-4516. 

Tetraglyme (2,5,8,11,14-pentaoxapentadecane) has been used in the hy-droxymethylation of aldehydes via addition of benzyl chloromethyl ether in the presence of Sml2. Addition of tetraglyme suppresses the competitive pinacol formation, presumably by a complex formation with Sml2 as evidenced by a purple color [25]. Tetraglyme has also been used as a cosolvent in an intramolecular Barbier reaction involving an iodoaldehyde and a THF solution of diiodosamar-ium [26]. 

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